Nitrotertiaryaminobenzonitriles



Patented Jan. 20, 1 953 NITROTERTIARYALIINOBENZONITRILES Raymond 0. Clinton, North Greenbush, and- Stanley 0. Laskowski, Menands, N. Y., assignors to Sterling Drug Inc., New York, N. Y., a cor poration of Delaware No Drawing. Application September 5, 1951, Serial No. 245,250

where X is a lower alkylene radical and NRR1 is a tertiary-amino radical.

These nitriles are also disclosed and are claimed in our copending application Serial No. 245,243, filed September 5, 1951.

The tertiary-aminoalkyl G-nitrobenzisoxazole- S-carboxylates used as starting materials in our process have the general formula C-COO-X-NRR1 where X is a lower alkylene radical and NRR1 is a tertiary-amino radical. These esters are also disclosed and are claimed in our copending application Serial No. 245,245, filed September 5, 1951.

In the above general formulas, the lower alkylene radical designated as X has preferably two to four carbon atoms and has its two free valence bonds on different carbon atoms. Thus, X includes such examples as CH2CH2-,

-CH2CH2CH2CH2--, CH2CH(CH3')CH2-, and the like. The tertiary-amino radical shown above as NRR1 comprehends dialkylamino radicals where R. and R1 are lower alkyl groups, alike or difierent, and each alkyl group having from two to six carbon atoms, such dialkylamino radicals including diethylamino, diisopropylamino, ethyl-n-propylamino, di-n-butylamino, di-n-hexylamino, and the like. Further, the tertiary- In particular, it relates to a method of amino radical designated as NRR1 encompasses saturated N-heteromonocyclic radicals having five to six ring atoms, illustrated by examples such as l-piperidyl; (lower-alkylated)-1-piperidyl such as Z-methyl-l-piperidyl, 3-ethy1-1- piperidyl, 4-methyl-1-piperidyl, 2,6-dimethyl-1- piperidyl; lpyrrolidyl; (lower alkylated)-1-pyrrolidyl such as 2 methyl 1 pyrrolidyl, 2,5- dimethyl-l-pyrrolidyl; 4-morpholinyl; and the like.

The process of our invention is carried out preferably by heating a tertiary-aminoalkyl G-nitrobenzisoXazole-3-carboxylate in a non-polar solvent such as toluene, benzene, xylene, a petroleum ether fraction, etc. Although the reaction is run preferably under anhydrous conditions, it can also be run in the presence of water, as illustrated below in the examples, however, with a decrease in yield of the 4-nitro-2-(tertiary-aminoalkoxy) benzonitriles, due to the formation of other products. Illustrative of our process is the formation of 4-nitro-2- (Z-diethylaminoethoxy) benzonitrile by heating 2-diethylaminoethyl G-nitrobenzisoxazole-3-carboxylate, preferably for a period of about twenty-four hours in toluene.

The conversion of a tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate into the corresponding 4-nitro-2- (tertiary-aminoalkoxy) benzonitrile is also efiected by merely allowing the tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate to be exposed to air at room temperature for a week or'so. However, under these mild conditions the reaction to form the corresponding 4-nitro-2- (tertiary-aminoalkoxy) benzonitrile proceeds only very slowly in low yield and is accompanied by undesirable side reactions. Thus, for better yields of the desired product the reaction is preferably carried out by heating the tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate, optimally at a temperature of about 50 C. to C.

' Alternatively, our process can be carried out without actually isolating the tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylates. This is done by heating a tertiary-aminoalkanol with a lower alkyl 6-nitrobenzisoxazole-B-carboxylate, preferably the methyl ester because of its relative ease of preparation. The tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate is formed first and then this ester, on continued heating, undergoes rearrangement to form the corresponding sults.

methylaminoethoxy)benzonitrile. Instead, only a 1,1AA-tetramethylpiperazinium salt of 4-nitro- Z-hydroxybenzonitrile was isolated.

The intermediate tertiary aminoalkyl G-nitrobenzisoxazole-3-carboxylatesare prepared by reacting a lower alkyl 6-nitrobenzisoxazole-3=car+ boxylate with a tertiary-aminoalkanol having the formula, HOX-NRR1, where X and NRR1 have the meanings given hereinabove. is carried out preferably using methyl G-nitrobenzisoxazole-3-carboxylate because of its ease; of preparation. The reaction is carried out preferably by heating a mixture of methyl 6-nitrobenzisoxazole-3-carboxylate and a tertiaryaminoalkanol. Illustrative of the reaction is the formation of Z-diethylaminoethyl 6-nitrobenzisoxazole-3-carboxylate by heating methyl 6-nitrobenzisoxazole-3-carboxylatewith Z-diethylaminoethanol. The reaction is carried out preferably by using a fractional distillation appara-, tus and a non-polar inert solvent such asbenzene, toluene, xylene, a petroleum ether frac-. tion, etc., so that heating could be stopped when the reaction was complete, asindicated, by the presenceof the theoretical quantity-of methanol (formed by the reaction) in the distillate. The reaction will proceed even though the methanol or lower alkanol is not removed by distillation, however, with a decrease in yield of the tertiaryaminoalkyl 6-nitrobenzisoxazole-3-carboxylates. A heating period of about one-half hour gives best yields of these intermediate tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylates.

Specific embodimentsof our invention areillustrated by the followingexamples.

I. Lower alkyl- 6-nitrobeneisoxazoZ-e-3 carboxylate Methyl 6-nitrobenzisoxazo1e-.3'-carboxylate was prepared from ethyl ZA-dinitrophenyIacetate according to the method of Borsche [Ann.. 390; 1 (1912)]. In order to achieve consistently the yield of 85% reported by Borsche, it was found necessary to use freshly prepared butyl'nitrite and an initial mixing temperature of 40 C. for the components. This ring closure procedure was also tried using other lower alkyl esters of 24- dinitrophenylacetic acid, however, with poor re- Using n-propyl, isopropyl and n-butyl esters of 2,4-dinitrophenylacetic acid, in their respective alkanols as solvents, only tarry products were obtained. Using ethyl 2,4-dinitrophenyl-r acetate in ethanol, a yield of about 20%,of ethyl 6-nitrobenzisoxazole-B-carboxylate was obtained. This ester recrystallized as yellow needles from ethanol, M. P. 99;0-'l00.0 C; (corn).

Anal. calcd. for C10H8N2O5' C., 5l.07; I-I, 3.43; Nuo 5.91; N 11.91.

Foun 0, 51.07; 11,-3.35; M0,, 6.04; ND, 12.15.

The reaction A better method for preparing the lower alkyl 6-nitrobenzisoxazole-3-carboxylates other than the methyl ester is afforded by the ester exchange reaction of methyl 6-nitrobenzisoxazole-3-carboxylate and the appropriate lower alkanol, as illustrated in the following preparation of ethyl fi-nitrobenzisoxazole-3-carboxylate using ethanol. A mixture of 40 g. of methyl fi-nitrobenzisoxazole-3-carboxylate, 300 ml. of anhydrous ethanol and 2 .ml. of triethylamine was boiled gently for twenty minutes.v The clear solution was; diluted while hot with an equal volume of water, cooled, filtered and the product was washed with water. The resulting material, after drying, was again treated-with anhydrous ethanol and triethylamine as before. There was thus obtained a nearly quantitative yield of ethyl G-nitrobenzisoxazole- 3-.carboxy1ate, M41. 99.0l00.0 C.

Following this procedure but using other lower alkanols in place of ethanol, the corresponding lower alkyl G-nitrobenzisoxazole-3-carboxylates are formed. Thus, using n-propanol, n-butanol oryisobutanol there is obtained, respectively, npropyl 6-nitrobenzisoxazole-3-carboxylate, n-butyl. fi-nitrobenzisoxazole-Bcarboxylate or isobutyl 6 nitrobenzisoxazole-S-carboxylate.

II. Tertiary-aminoalkyl 6-nitrobenzz'soxazole 3-carboxylates Preparation of these esters, in the form of their hydrochlorides, is illustrated by the following generalprocedure. A mixture of 44.4 g. (0.2 mole) of methyl '6-nitrobenzisoxazole-3-carboxylate, 0.22 mole of the appropriate tertiary-aminoalkanol and 350 m1. of dry toluene was distilled slowly through a 14" vacuum-jacketed Vigreux column surmounted by a total-reflux variable take-off distillation head. During one-half hour twelve to sixteen ml. of distillate were collected, the final distillate temperature being C. The pale yellowebrown still residue was decolorized using decolorizing charcoal and the toluene was removed. in vacuo. The residue was dissolved in ethyl acetate and the solution was treated with an excess of 20% ethereal hydrogen chloride. The precipitated white solid was recrystallized from. ethanol or isopropanol. The yields of the purified tertiary aminoalkyl fi-nitrobenzisoxazole-3-carboxylates in the form of their hydrochlorides were-65 75%'.

The same products result when the above procedure is followed but using-other alkyl esters such as ethyl or n-butyl 6-nitrobenzisoxazole-3- carboxylateinplace of methyl-6 -'nitrobenzisoxazole-B-carboxylate.

When the above procedure was followed using '2-=diethylaminoethanol as the tertiary-aminoalkanol, the resulting product was 2-diethyl-.- aminoethyl 6-nitr0benzisoxazole-3-carboxylate. Use of other tertiary-aminoalkanols yield the corresponding tertiary-aminoalkyl esters in the form of their hydrochlorides as given in Table A below.

The free base form of a given ester was conveniently prepared by dissolving a portion of the hydrochloride salt in ice water and treating the solution-with an excess of cooled, saturated sodium bicarbonate solution. The precipitated oily or crystalline base was taken up in cold ethyl acetate, the extract was dried and the tertiaryaminoalkyl 6-nitrobenzisoxazole-3- carboxylate was obtainedby removing the ethyl acetate in vacuo..

. "TABLE'A.

To ownomnapnol QzN 0/ I Analyses V I M. P. 0.

n NRR; I (00k) Formula 01 N o Calcd Found Oalcd. Found 2 N(OH3)2 172. 0-173. 0 .CmHnNsOaHCl 11. 23 11. 22 2 N(C2H5)2 151. 8-153. 0 C14H17NaO5.HC1 10. 31 10.32 4. 07 4.04 3 N C2H5)z 151. -151. 8 CltHlQNGOt-HCI 9. 91 9. 97 3. 92 3. 99 2 N H o 160. l-l61. 0 C15H NsO5.HC1 9.97 10.02 3. 94 3. 84 2 NCaHm' 151. 0-151. 5 O18HNN305.HC1 9. 59 9. 69 3. 79 3. 74 3 NC5H10 189. 9-190. 3 C1aH1nNaO5.HO1 9. 59 9. 44 3. 79 3. 70 3 NCeHm" 157. 8-158. 7 C17H21N306.HC1 9. 24 9. 3. 65 3. 63

With decomposition.

' Calcd; C, 45.65; H, 4.47. Found: C, 45.74; H, 4.75. sH1o=1-piper' 1 III. 4 mtro 2 (tertiary-aminoalkoxy)benzonitriles from purified tertiaryaminoalkyl 6- nitrobenzisoxazoZe-B-carboa:ylates Preparation of 4-nitro-2-(tertiaryaminoalkoxy)benzonitriles from the corresponding purified tertiary-aminoalkyl 6-nitrobenzisoxazole-3- carboxylates is illustrated by the following specific examples.

4 nitro-2-[2-(1 piperidyl)ethoxylbenzonitrile was obtained from 2-(1-piperidyl)ethyl 6- nitrobenzisoXazo1e-3-carboxylate as follows: To a solution of 31.5 g. of 2-(1-piperidyl)ethyl 6- nitrobenzisoxazole-3-carboxylate in 400 ml. of cold water was added an excess of solid sodium bicarbonate. The precipitated base was extracted with cold toluene, and the clear pale yellow toluene solution was dried over two successive portionsof anhydrous calcium sulfate at 10C. Under these conditions no decomposition of the free base was noted. A small aliquot portion of the filtered solution was placed in a crystallizing dish and allowed to evaporate in-the air (vide infra), and the remainder was refluxed under anhydrous conditions for twentyfour hours. During this entire period carbon dioxide was slowly but steadily evolved; the solution at the end of twenty-four hours was dark orange-brown in color, but clear and homogeneous. The toluene was removed in vacuo and the residual solid was recrystallized from nheptane with decolorization. The pale yellow product was heated with 500 ml. of aqueous 4% hydrochloride sodium hydroxide solution in order to destroy unreacted 2-(1-piperidyl)ethyl G-nitrobenzisoxazole-3-carboxylate. From this treatment, after recrystallization of the sodium hydroxide-insoluble material from ethyl acetate-n-hexane, was obtained at 51.7% yield of 4-nitro- 2-[2-(1-piperidyl) ethoxylbenzonitrile, M. P. 118.1-119.2 C. (cor).

NBA stands for basic amino nitrogen as determined by ggililration with perchloric acid in glacial acetic acid solu- Anal. calod. for CnHrzNaOa NBA, 5.09; NN02, 5.09. Found NBA, 507; NN02, 5.05.

The aliquot portion of the toluene solution which had been removed above was allowed to stand in the air for eight days. During this period the initially yellow crystalline base sintered to an orange sticky paste, then resolidified slowly to a spongy orange solid. From this material were obtained, by the procedure described below under Example IV: 4-nitro-2-[2-(1-piperidyDethoxylbenzonitrile (about 5% yield), isolated as the picrate, 4-nitro-2-[2-(l-piperidyl)- ethoxy] benzonitrile di- 2-cyano-5-nitrophenolate) (about 5% yield), and 2-(1-piperidyl)ethanol mono-(2-cyano-5-nitrophenolate) (about yield), yellow-orange prisms from ethyl acetate-n-hexane, M. P. 85.0-86.3 C. (0013.)

Anal. calcd. for C14H19N304 NBA, 4.78; Nno 4.78. Found ..NBA, 4.68; NNO2, 4.82.

4 nitro-2 [3-(1-piperidyl)propoxylbenzonitrile, M. P. 102.2-102.8 C. (cor.), was prepared from 3-(1-piperidyl) propyl 6-nitrobenzisoxazole- 3-carboxylate according to the procedure described above in the preparation of the corresponding 4-nitro-2- [2- (1 -piperidyl) ethoxyl] benzonitrile. A 29.5% conversion of the tertiaryaminoalkyl ester was obtained in twenty-four hours.

Anal. calcd. fOI' C15H19N303 NBA, 4.84; Nno 4.84. Found NBA, 4.87; NNO2, 4.80.

From a portion of the 3-(1-piperidyl)propyl G-nitrobenzisoxazole-3-carboxylate which had been allowed to stand in air for eight days was isolated, according to the procedure described above, only a very small amount of 4-nitro-2-[3- l-piperidyl) propoxy] benzonitrile, 4-nitro-2- [3- (1 piperidyl) propoxylbenzonitrile mono (2- cyano- 5-nitrophenolate) (about 2% yield), and

7 3- l-piperidyl) propanol di- (2-cyano-5-nitrophenolate) (about 95% yield).

4 nitro 2 (2 diethylaminoethoxy) benzonitrile was obtained from Z-diethylaminoethyl 6- nitrobenzisoxazole-3-carboxylate in a 71% yield, following the above procedure described for the preparation of 4-nitro -2- 2- l-piperidyl) ethoxylbenzonitrile. 4 nitro 2-(2-diethylaminoethoxy)benzonitri1e, in the form of itshydrochloride salt, melted at 192.0l93.0C. (corn) Anal. calcd. for C13H1'1N303.HC1

TC1,,11 83; N ,.1.4.02. Found Cl, 11.75.; N 14.0.2.

When Z-diethylaminoethyl fi-nitrobenzisoxazole-3-carboxylate, in the formof its,:free base, was allowed to stand in the airforten days, it was converted into 4-nitro-y2-(Z-diethylaminoethoxy)benzonitrile (about 8% yield), 4-nitro- 2 (2 diethylaminoethoxy)benzonitrile di (2 cyano--nitrophenolate) (about 10% yield), 2- diethylaminoethanol (about 80% yield), isolated as the picrate, and a trace of a red-colored unbenzomtrllwizMnP. 133.4136.2 C. (con), was obtained in a yield ofabout 22% when the above procedure was 'followedzbut using 2- (2-methyl-1- piperidyl) ethylfi 6-nitrobenzisoxazole-3-carboxylate instead of the. corresponding 2-(1-piperidyl) ethyl ester and using a one mole proportion of water in addition to thetoluene.

.Anal. calcd. for CH19N3O3 .C, 62.26;.H; 6. .62; NBA, 4.84; N 151.52.

-Eound c, 62.38; H, 6:53 1234.482; ND, 14.24.

known compound having a .imelting pointj'o'f 2060 201090.

4 -nitro-2-[2-.(2=methyl-1 piperidyD-ethoxy] Hydrocmorideadditiom salts of-:-:.the;above 4- ltm-Zaltertiarseaminoalkoxya.benzonitriles are venjn. IableC.

7 Analyses, Percent NRR1 gm Formula ..Gl. I 'Nno,

Qalcd ,Eound Oalcd Bound 3 Naomi), 210. 2-210.9 CHHIQNQOE, 11,01 v11.30 1 4.46 4.52 2 EH10 v H ITNQ'OaTHCT 11.33 4:49 4.64 2 NC' Hm 192. 7:19am QuHwNgQa. H01 310.80 112.90 4.151204 2 NO1H14 214. 6-215. .3 GmHnNa0;. .H.C1 .10. 4.12 4. 26

3 NC5H16 194. 0-1940 015111911303. H01 10$ 83' 4.- 30 4530 v3 .NCAHH 1811:1880 $TC1H21N3O3.HC1 10. 27 4.41237 412.12 2 NCIHSOI .214. 62l5.5 O13H15N30111Q1 .1131 4. 47 4.36 '3 12012210 2150-2152 'C14H11NaO4.HOl 10.85' 4:27 4.19'

I N (3 1150 =4-morpholinyl.

'- Other 4-nitro-2-.- (tertiary-aminoalkoxy) benzo- 4-m'tro- 2 (tertiary-aminoalkoary)benzonitriles without isolating the tertiary-aminoalkyl 6-nitrobenziso:cazole-3-carbomylates The 4-nitro-2- (tertiary-aminoalkoxy) benzonitriles are also formed by heating a lower alkyl 6- nitrobenzisoxazole-3-carhoxylate, preferably the methyl ester, with a tertiary-aminoalkanol, without isolating the intermediate tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate thereby formed. This procedure is illustrated using the following tertiary-aminoalkanols.

2-diethyZaminoethanol.-A mixture of 66.6 g. (0.30 mole) of dry methyl G-nitrobenzisoxazole- 3-carboxylate, 38.7 g. (0.33 mole) of Z-diethylaminoethanol and 1200 ml. of dry toluene was distilled slowly through a 14" vacuum-jacketed Vigreux column surmounted by a total-reflux variable take-off distillation head. A total of 300 m1. of distillate was collected during seven hours. The evolved gases were trapped and tested; carbon dioxide was shown to be evolving steadily throughout the reaction,- but carbon monoxide and unsaturates were absent. During this distillation the still contents darkened to brown. The toluene was removed from the still residue in vacuo and the residual yellow-brown solid was treated as follows:

A weighed portion was extracted several times with hot n-heptane and the combined n-heptane extracts were decolorized and cooled. The crystalline product, after several recrystallizations from absolute alcohol, formed shiny yellow plates, M. P. 104.5-105.5 C. The compound was stable towards hot 4% aqueous sodium hydroxide solution (differentiation from methyl fi-nitrobenzisoxazole-3-carboxylate or 2-diethylaminoethyl 6- nitrobenzisoxazole 3 carboxylate) and readily gave a crystalline picrate (M. P. 1701-1708? C.) and hydrochloride (M. P. 193.0-194.0 C.). A mixed M. P. of the pure base with pure 4-nitro-2- (Z-diethylaminoethoxy)benzonitrile, prepared as above in Example III, showed no. depression. Similarly, the mixed melting points of the corresponding picrates and hydrochlorides were undepressed.

Anal. calcd. for CisHnNsOsi C, 59.30; H, 6.51; N 5.32; N 5.32; mol. wt. 263.

Found: C, 59.43; H, 6.55; N 5.32; N .5.-28; mol. wt. (cryoscopic in dioxane) 271. The weight of 4-nitro-2- (Z-diethylaminoethoxy) benzonitrile obtained corresponded to a 67% conversion of the methyl 6-nitrobenzisoxazolee3-carboxylate.

A twenty gram portion of the above residual yellow-brown solid was allowed to stand at room temperature in the open air for eight days. The solid material slowly sintered to a sticky, bright orange paste. The material was extracted three times with boiling n-heptane (from the n-heptane extracts was recovered 13.6 g. of pure 4-ni tro-2- (2-diethylaminoethoxy) benzonitrile) The n-heptane-insoluble material was, suspended in warm ethyl acetate and the insoluble red precipitate was removed by filtratiom The ethyl acetate solution was decolorized and cooled well in ice. The resulting crystalline precipitate was collected and washed thoroughly with a cold one to one mixture of n-hexane-ethyl acetate. Further recrystallization from an ethyl acetate-n-hexane mixture gave 4.2 g. of 4-nitro-2-(2-diethylamino- .ethoxy)benzonitrile di (2-cyano-5-nitrophenolate), crystallizing in rosets of brilliant yelloworange needles, M. P. 146.9-1474 C. When mixed with a synthetic sample of 4-nitro-2-(2-diethyl aminoethoxy) benzonitrile di-(2-cyano 5 nitrophenolate) this product (orange-yellow needles) gave no depression of melting point.

The solution in ethyl acetate when treated with ethereal hydrogen chloride yielded crystalline 4 nitro 2 (2-diethylaminoethoxy) benzonitrile hydrochloride, M. P. 193.2-194.4 C., which showed no depression of melting point on admixture with a sample of 4-nitro-2-(Z-diethylaminoethoxy)- benzonitrile hydrochloride obtained as shown hereinabove. From the mother liquors from this treatment was isolated a compound melting at 161-162" C. This compound was 4-nitro-2-hydroxybenzonitrile since it showed no M. P. depression on admixture with a'sample of pure 4-nitro-2-hydroxybenzonitrile.

A further portion of the original yellow-brown reaction product was powdered and extracted several times with warm 15% aqueous sodium bi sulfite solution. From the solution was recovered, by treatment with 35% aqueous sodium hydroxide solution, pure 4-nitro-2-(2-diethylaminoethoxy)benzonitrile. The insoluble material was dried, extracted several times with boiling ethyl acetate (extracts discarded) and recrystallized from hot water. The product crystallized in white cottony needles, M. P. 220.2-220.6 (dec.). A mixed melting point with a syntheticspecimen of 4-nitro-2- (Z-diethylaminoethoxy) benzonitrile bisulfite, prepared from the base, sodium bisulfite solution and a few drops of acetic acid, showed no depression.

Anal. calcd. for C13H19N306S C, 45.21; H, 5.54; NBA, 4.06; N1),1 2.17; S, 9.28. Found C, 45.58} H, 5.46; NBA, 3.85; ND, 12.07; S, 9.48.

3-(2-methyl-1-piperidyl) propanol-A mixture of 44.4 g. (0.20 mole) of methyl G-nitrobenzisoxazole-3-carboxylate, 39.2 g. (0.25 mole) of redistilled 3-(2-methyl-l-piperidyl) propanol and 350 ml. of dry toluene was refluxed with slow distillation (vide supra) for six hours. The toluene was removed from the dark brown still contents in vacuo, and the residual brown oil was triturated with several portions of n-pentane (the insoluble portion was shown to be methyl G-nitrobenzisoxazole-3-carboxylate) A portion of the n-pentane solution on evaporation, followed by recrystallization of the residual solid several times from n hexane with decolorization, gave a yield of about 15% of a compound crystallizing in pale yellow leaflets, M. P. 93.1-93.9". The mixed melting point with pure 4 nitro 2 [3-(2-methyl-1-piperidyl)propoxyl-benzonitrile, prepared above in "Example III, was undepressed, and the mixed melting point of the corresponding picrates showed no depression.

Anal. calcd. for C16H21N303 NNO2, 4.62; NBA, 4.62. Found .NNO2, 4.72; NBA, 4.63.

A further portion of the n-pentane solution was evaporated to dryness and the residual :cnude solid wasallowed to stand in the open :air at room temperature for eight days. The spongy resinous orange solid was then extracted several times with hot n-hexane (extracts discarded). The insoluble material was dissolved in ethyl acetate and'the solution wasdecolorized. A small portion-ofthis solution on treatmentwith anequal volume of n-hexane gave an orange precipitate. The latter, when recrystallized from :a small -vol-- ume of ethyl acetate,-formed orange needlesmelting at 131.6-132.-8 and showing no depression of melting point on admixture with a synthetic sample of 4-nitro-2-[3-(2-methyl-l-piperidyl) propoxylbenzonitrile mono- 2 --cyano--nitrophenolate). Further, treatment of =this=orange solid with ethereal hydrogen chloride yielded pure 4 nitro 2- [3- (Z-methyl-l-piperidyl) propoxylbenzonitrile hydrochloride and pure-4-nitro-2- hydroxybenzonitrile, as shown by mixed melting points.

2-(I-piperidyllethand. This reaction was carried-out in the manner described above for Z-diethylaminoethanol. The reaction products were isolated by'similar'methods. In-each case the structures wereshown' by analyses, by degradation, andby mixed meltingpoints-with:synthetic samples. There were-obtained: 4-nitro 2- [2- (1-piperidy1)ethoxylbenzonitrile, :in amount corresponding to a 38% conversion of methylenitrobenzisoxazole-Bcarboxylate, and '4-nitro-2- [2-'( I-piperidyDethOXyJbenzonitrile di(2-cyano- 5-nitrophenolate), from moisture degradation-of the crude reaction product.

"The foregoing procedure of heating raxlower alkyl 6-nitrobenzisoxazole -carboxylate with a tertiary-aminoa'lkanol can be carriedbut using other tertiary' aminoalkanols in addition to :the ones shown above -in the specific illustrations. Thusgby heating methyl or-ethyl fi-nitrobenzisoxazole-3-carboxylate with 3-(1-pyrrolidyl) propanol, 2- (2,5-dimethyl-l-pyrrolidyl) ethanol, .4-diethylaminobutanol, 2-di-nbutylaminoethanol; or 3- (2-methyl-1-pyrro1idyl) -propanol', :there is obtained, respectively, 4 -nitro-2- [3 (1 -pyrrolidyl) propoxy] benzonitrile, 4-.-nitr.o-2- [2- (2,5-dimethyl- 1 pyrrolidyl) ethoxy] benzonitrile, 4-nitro-2- (4- diethylaminobutoxy) benzonitrile, 4 nitro-2-(2- di-n-butylaminoethoxy) benzonitrile or 4-nitro-2- [3- (Z-methyl-l -pyrrolidyl) propoxy l-benzonitrile.

We claim:

1. The process of preparing a compound having the formula where)! is a lower alkylene-radical whose 'two free valence bonds are-on different carbon atoms and NRR1 is a member of the group consisting of lower dialkylamino where each 'alk-yl -radical has from two tosix carbon atoms, tl-piperidyl, (lower .alky-lated) --1..- piperidyl, 1 pyrro1idyl, (lower :alkylatedl-lepyrrolidyl and :t-mcmholinyl, which comprises heating a tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate having the formula 1 2 1'2. i'rheprocesscfpreparinga-ccompoundhaving the formula C GLOQfXv NRR Dl I o 3. The process of preparing a-com-pound having theformula where X is a lower valkylene radical whose two free valence bonds are on difierent carbon atoms and NRR1 ,is a ,zemethylal-pip ridyl radical, which comp ises heating a .tertiaryaaminoalky l6 mtrObenZiSQXaZQIe-B-carboxylate having the formula 0-0 0 OXNRR1 OZN 4. Thevprocess of preparinga compound having the formula IITO:

where X is a lower alkylene radical whose two free valence bonds are on diiferent carbon atoms and NRRl'iS a l-piperidyl radical, which comprises heating a tertiary aminoalkyl 6-nitr0- benzisoxazole-3-carboxylate having the formula (MN I 0/ 5. The process of preparing a compound having the formula and each lower alkyl radical has from two-to six carbon atoms, which comprises heating a 13 dialkylaminoalkyl 6-nitrobenzisoxazo1e 3 carboxyiate having the formula t 0-0 0 0X-N (lower a1kyl)2 6. The process of preparing a compound having the formula where X is a lower alkylene radical whose two free valence bonds are on difierent carbon atoms, which comprises heating a diethylaminoalkyl 6- nitrobenzisoxazole-3-carboxy1ate having the formula OzN 0 No references cited. 

1. THE PROCESS OF PREPARING A COMPOUND HAVING THE FORMULA 